Hypertrophic cardiomyopathy is characterized by a hypertrophied non-dilated left ventricle and has been considered to be largely a disease of cardiac muscle. To assess the possibility that the mitral valve itself may be primarily involved in the cardiomyopathy disease process, we performed gross and histologic analyses on mitral valves from 94 patients with hypertrophic cardiomyopathy and 45 normal controls. Area of the mitral valve was increased in patients with hypertrophic cardiomyopathy compared to controls (12.9 +- 3.7 vs 9.1 +- 2.2 cm2; p < 0.001). This increase in mitral valve size was due primarily to an increase in leaflet length (2.2 +- 0.5 for anterior leaflet vs 1.7 +/- 0.3 cm for controls; p < 0.001), since circumference did not differ between the two groups. Of the 94 patients, the mitral valve was increased in area -> 12.0 cm2 in 55 (or 58%). In 12 of these 55 valves, both the anterior and posterior leaflets were enlarged; the other 43 valves with increased overall area showed asymmetric or segmental enlargement of either the anterior leaflet (36 patients) or the mid-scallop of the posterior leaflet (7 patients). Multiple regression analyses showed that variation in mitral valve area was largely independent of other clinical or morphologic components of the disease process. Mitral valve area was mildly but significantly associated only with gender and body height and these relationships accounted for only 20% of the variability identified in valve size. The observations and findings presented here strongly support the concept that the disease process in hypertrophic cardiomyopathy is not confined to the left ventricular myocardium and a primary congenital abnormality of mitral valve structure is characteristic of the majority of patients with this disease.